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Cited by 339Liver Disease and TransplantationGastrointestinal Bleeding Diagnosis and TreatmentAbdominal vascular conditions and treatments

Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis

Abraldes, Juan G., Villanueva, Candid, Aracil, Carles, Turnes, Juan, Hernandez-Guerra, Manuel, Genesca, Joan, Rodriguez, Manuel, Castellote, Jose +39 more·2016·Gastroenterology
DOI 10.1053/j.gastro.2016.01.004
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Abstract

Background & aims The combination of β-blockers and band ligation is the standard approach to prevent variceal rebleeding, but bleeding recurs and mortality is high. The lipid-lowering drug simvastatin decreases portal pressure, improves hepatocellular function, and might reduce liver fibrosis. We assessed whether adding simvastatin to standard therapy could reduce rebleeding and death after variceal bleeding in patients with cirrhosis.Methods We performed a multicenter, double-blind, parallel trial of 158 patients with cirrhosis receiving standard prophylaxis to prevent rebleeding (a β-blocker and band ligation) in Spain from October 2010 through October 2013. Within 10 days of bleeding, subjects were randomly assigned, but stratified by Child-Pugh class of A or B vs C, to groups given simvastatin (20 mg/d the first 15 days, 40 mg/d thereafter; n = 69) or placebo (n = 78). Patients were followed for as long as 24 months. The primary end point was a composite of rebleeding and death, and main secondary end points were the individual components of the composite (death and rebleeding).Results The primary end point was met by 30 of 78 patients in the placebo group and 22 of 69 in the simvastatin group (P = .423). Seventeen patients in the placebo group died (22%) vs 6 patients in the simvastatin group (9%) (hazard ratio for adding simvastatin to therapy = 0.39; 95% confidence interval: 0.15-0.99; P = .030). Simvastatin did not increase survival of patients with Child-Pugh class C cirrhosis. Rebleeding occurred in 28% of patients in the placebo group and 25% in the simvastatin group (P = .583). Serious adverse events occurred in 53% of patients in the placebo group and 49% in the simvastatin group (P = .752); the percentages of serious adverse events related to therapy were 11% in the placebo group vs 8% in the in the simvastatin group (P = .599). Two patients in the simvastatin group, each with advanced liver disease, developed rhabdomyolysis.Conclusions In a randomized controlled trial, addition of simvastatin to standard therapy did not reduce rebleeding, but was associated with a survival benefit for patients with Child-Pugh class A or B cirrhosis. Survival was not the primary end point of the study, so these results require validation. The incidence of rhabdomyolysis in patients receiving 40 mg/d simvastatin was higher than expected. European Clinical Trial Database ID: EUDRACT 2009-016500-24; ClinicalTrials.gov ID: NCT01095185.

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Crossref · 10.1053/j.gastro.2016.01.004

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  • In patients under secondary prophylaxis of variceal bleeding, the addition of statin therapy to standard of care has shown a survival benefit in patients with Child-Pugh class A or B cirrhosis.

    “Most importantly in patients under secondary prophylaxis of variceal bleeding, the addition of statin therapy to standard of care has shown a survival benefit in patients with Child‐Pugh class A or B cirrhosis; [93] however, only five patients with NAFLD have been included in this study.”

    From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [93]

  • In the statin trial, no statistical difference was seen between the simvastatin and placebo arm, however, rhabdomyolysis occurred in two (2.8%) patients.

    “In regard to adverse events, no statistical difference was seen between the simvastatin and placebo arm, however, rhabdomyolysis occurred in two (2.8%) patients [93].”

    From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [93]

  • Only five patients with NAFLD have been included in the statin survival study.

    “Most importantly in patients under secondary prophylaxis of variceal bleeding, the addition of statin therapy to standard of care has shown a survival benefit in patients with Child‐Pugh class A or B cirrhosis; [93] however, only five patients with NAFLD have been included in this study.”

    From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [93]

  • One RCT testing simvastatin in individuals with variceal haemorrhage failed to show an impact on rebleeding.

    “One RCT testing simvastatin in individuals with variceal haemorrhage failed to show an impact on rebleeding and suggested an improvement in overall survival, and the drug was safe in this high-risk population. 471”

    From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [471]

  • Simvastatin was safe in individuals with variceal haemorrhage.

    “One RCT testing simvastatin in individuals with variceal haemorrhage failed to show an impact on rebleeding and suggested an improvement in overall survival, and the drug was safe in this high-risk population. 471”

    From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [471]

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Authors
Abraldes, J. G., Villanueva, C., Aracil, C., Turnes, J., Hernandez-Guerra, M., Genesca, J., Rodriguez, M., Castellote, J., García-Pagán, J. C., Torres, F., Calleja, J. L., Albillos, A., Bosch, J., Augustin, S., Llop, E., Arraez, D. M., Hernández Mesa, G., Martinez, J., Reverter, E., Seijo, S., Turon, F., Miñana, J., Buenestado, J., Reñe, J. M., Navacués, C. A., Planas, R., Morillas, R. M., Bellot, P., Such, J., Vergara, M., Puente, A., de la Pena, J., Mera Calviño, J., Rivas Moral, L., Pavel, O., Alvarado, E., Ardevol, A., Girbau, A., Cachero, A., Arnaiz, J. A., Berzigotti, A., Pich, J., Rios, J., Saenz, R., Millan, L., Beleta, H., & Ramos, N.
Affiliations
  • Hospital Universitari Arnau de Vilanova (ES)
  • University Hospital of Bern (CH)
  • Hospital Clínic de Barcelona (ES)
Corresponding author
Bosch, Jaime
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2016-05
Volume
150
Issue
5
Pages
1160-1170.e3
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2016.01.004
OpenAlex
W2234170759
Cited by
339
References
51
Citations by year
2026: 22 · 2025: 27 · 2024: 30 · 2023: 33 · 2022: 31 · 2021: 35 · 2020: 35 · 2019: 34 · 2018: 30 · 2017: 38 · 2016: 23 · 2014: 1
FWCI
30.09
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion)
Funders
National Institute on Alcohol Abuse and Alcoholism (U01AA021908)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal Bleeding Diagnosis and Treatment
  • Health Sciences › Medicine › Surgery › Abdominal vascular conditions and treatments
Keywords
simvastatin, variceal rebleeding, liver cirrhosis, portal hypertension, variceal bleeding, survival, beta-blockers, band ligation, Child-Pugh score, serious adverse events, lipid-lowering drugs, portal pressure, liver fibrosis, hepatocellular function, drug repurposing
MeSH terms
Adrenergic beta-Antagonists, Aged, Combined Modality Therapy, Double-Blind Method, Esophageal and Gastric Varices, Female, Gastrointestinal Hemorrhage, Humans, Ligation, Liver Cirrhosis, Male, Middle Aged, Recurrence, Rhabdomyolysis, Risk Factors, Spain, Time Factors, Proportional Hazards Models, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Kaplan-Meier Estimate

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